Pleiotropic mechanisms have been implicated in Alzheimer's disease (AD), including transcriptional dysregulation, protein misprocessing and synaptic dysfunction, but how they are mechanistically linked to induce cognitive deficits in AD is unclear. Here we find that the histone methyltransferase Smyd3, which catalyzes histone H3 lysine 4 trimethylation (H3K4me3) to activate gene transcription, is significantly elevated in prefrontal cortex (PFC) of AD patients and P301S Tau mice, a model of tauopathies. A short treatment with the Smyd3 inhibitor, BCI-121, rescues cognitive behavioral deficits, and restores synaptic NMDAR function and expression in PFC pyramidal neurons of P301S Tau mice. Fbxo2, which encodes an E3 ubiquitin ligase controlling the degradation of NMDAR subunits, is identified as a downstream target of Smyd3. Smyd3-induced upregulation of Fbxo2 in P301S Tau mice is linked to the increased NR1 ubiquitination. Fbxo2 knockdown in PFC leads to the recovery of NMDAR function and cognitive behaviors in P301S Tau mice. These data suggest an integrated mechanism and potential therapeutic strategy for AD.
Keyphrases
- prefrontal cortex
- mouse model
- high fat diet induced
- poor prognosis
- cerebrospinal fluid
- end stage renal disease
- dna methylation
- ejection fraction
- traumatic brain injury
- chronic kidney disease
- gene expression
- newly diagnosed
- oxidative stress
- transcription factor
- wild type
- type diabetes
- spinal cord
- prognostic factors
- signaling pathway
- binding protein
- genome wide
- machine learning
- metabolic syndrome
- copy number
- long non coding rna
- deep learning
- heat stress
- small molecule
- patient reported
- smoking cessation